1. Dichotomous metabolic networks govern human ILC2 proliferation and function
- Author
-
Carys A. Croft, James P. Di Santo, Antonia Cama, Solenne Marie, Carmen Buchrieser, Davide Topazio, Olimpia Musumeci, Valerie Dardalhon, Laura Surace, Naomi Taylor, Jean-Marc Doisne, Vincent Guillemot, Natalia Petrosemoli, Pedro Escoll, Ido Amit, Anna Thaller, Immunité Innée - Innate Immunity, Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), École Doctorale Bio Sorbonne Paris Cité [Paris] (ED562 - BioSPC), Université Sorbonne Paris Cité (USPC)-Université Paris Cité (UPCité), Biologie des Bactéries intracellulaires - Biology of Intracellular Bacteria, Université Paris Cité (UPCité)-Microbiologie Intégrative et Moléculaire (UMR6047), Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Hub Bioinformatique et Biostatistique - Bioinformatics and Biostatistics HUB, Institut Pasteur [Paris] (IP)-Université Paris Cité (UPCité), Institut de Génétique Moléculaire de Montpellier (IGMM), Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Department of Otolaryngology, Ospedale 'Giuseppe Mazzini' di Teramo, Department of Maxillofacial and Otolaryngology, Hospital 'Floraspe Renzetti', Department of Immunology [Rehovot, Israël], Weizmann Institute of Science [Rehovot, Israël], Department of Clinical and Experimental Medicine [Messina, Italy], University of Messina, The Innate Immunity Unit is supported by grants from the Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Pasteur, the Agence National pour le Recherche (ANR) and the European Research Council (ERC) under the European Union’s Horizon 2020 research and innovation program (695467, ILC_REACTIVITY). A.T. is supported by European Union’s Horizon 2020 research and innovation program under the Marie Skłodowska-Curie grant agreement no. 765104. C.B.’s group was supported by the Fondation pour la Recherche Médicale (FRM) grant no. EQU201903007847 and the grant no. ANR-10-LABX-62-IBEID. L.S. was supported by an SNSF-Early PostDoc. Mobility fellowship and a Marie Curie grant (H2020- MSCA-IF-2017)., We thank all the members of the Innate Immunity Unit for helpful discussions, the Centre de Recherche Translationnelle and the logistic department of Institut Pasteur. We thank the CB-UTechS platform for cytometry support and the Imagopole-CiTech (part of France-BioImaging supported by ANR grant no. ANR-10-INSB-04-01, Conseil de la Region Ile-de-France, FRM) for technical support., The study was conceptualized by L.S. and J.P.D. Experiments were coordinated by L.S. FACS and subsequent analyses were performed by L.S., C.A.C., A.T., J.-M.D. and S.M. Confocal microscopy analysis was performed by P.E., C.B. and L.S. Bioinformatic analyses were performed by N.P. and V.G. RNA-seq experiments were conducted by I.A. O.M., V.D., N.T., D.T. and A.C. provided resources. L.S. and J.P.D. wrote the paper. Funding was acquired by L.S. and J.P.D., and the study was supervised by J.P.D., ANR-10-INBS-0004,France-BioImaging,Développment d'une infrastructure française distribuée coordonnée(2010), ANR-10-LABX-0062,IBEID,Integrative Biology of Emerging Infectious Diseases(2010), European Project: 695467,H2020-EU.1.1. - EXCELLENT SCIENCE - European Research Council (ERC) ,ILC_REACTIVITY(2016), European Project: 765104,MATURE-NK, European Project: 796004,BIF-SCV, Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), École Doctorale Bio Sorbonne Paris Cité [Paris] (ED BioSPC), Université Sorbonne Paris Cité (USPC)-Université de Paris (UP), Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM), and Hospital 'Giuseppe Mazzini'
- Subjects
Letter ,Mitochondrial Diseases ,Lymphocyte Activation ,0302 clinical medicine ,Immunology and Allergy ,Glycolysis ,Receptor ,Tissue homeostasis ,Cells, Cultured ,0303 health sciences ,MESH: Cytokines ,Innate lymphoid cell ,MESH: Energy Metabolism ,MESH: Arginine ,MESH: Mitochondrial Diseases ,MESH: Case-Control Studies ,Cell biology ,Mitochondria ,Phenotype ,[SDV.IMM]Life Sciences [q-bio]/Immunology ,Cytokines ,MESH: Immunity, Innate ,MESH: Cells, Cultured ,MESH: Interleukin-33 ,MESH: Mitochondria ,Immunology ,Innate lymphoid cells ,Oxidative phosphorylation ,Biology ,MESH: Phenotype ,Arginine ,03 medical and health sciences ,Th2 Cells ,MESH: Th2 Cells ,MESH: Cell Proliferation ,Humans ,MESH: Lymphocyte Activation ,PI3K/AKT/mTOR pathway ,030304 developmental biology ,Cell Proliferation ,MESH: Humans ,Interleukins ,Metabolism ,Interleukin-33 ,Immunity, Innate ,Metabolic pathway ,Case-Control Studies ,Energy Metabolism ,Amino Acids, Branched-Chain ,030215 immunology ,MESH: Amino Acids, Branched-Chain - Abstract
Group 2 innate lymphoid cells (ILC2s) represent innate homologs of type 2 helper T cells (TH2) that participate in immune defense and tissue homeostasis through production of type 2 cytokines. While T lymphocytes metabolically adapt to microenvironmental changes, knowledge of human ILC2 metabolism is limited, and its key regulators are unknown. Here, we show that circulating ‘naive’ ILC2s have an unexpected metabolic profile with a higher level of oxidative phosphorylation (OXPHOS) than natural killer (NK) cells. Accordingly, ILC2s are severely reduced in individuals with mitochondrial disease (MD) and impaired OXPHOS. Metabolomic and nutrient receptor analysis revealed ILC2 uptake of amino acids to sustain OXPHOS at steady state. Following activation with interleukin-33 (IL-33), ILC2s became highly proliferative, relying on glycolysis and mammalian target of rapamycin (mTOR) to produce IL-13 while continuing to fuel OXPHOS with amino acids to maintain cellular fitness and proliferation. Our results suggest that proliferation and function are metabolically uncoupled in human ILC2s, offering new strategies to target ILC2s in disease settings., ILC2 metabolism has been largely unexplored. Di Santo and colleagues examine metabolic profiles from naive and cytokine-activated ILC2s and find that IL-33-triggered ILC2s rely on distinct metabolic pathways to sustain proliferation and function.
- Published
- 2021
- Full Text
- View/download PDF